Marija Bojic

Cardiac Toxicity of Sunitinib and Sorafenib in Patients With Metastatic Renal Cell Carcinoma

PURPOSE Sunitinib and sorafenib are tyrosine kinase inhibitors (TKIs) that have considerable efficacy in metastatic renal cell carcinoma. TKI-associated cardiotoxicity was reported in approximately 10% of the patients. Detailed cardiovascular monitoring during TKI treatment may reveal early signs of myocardial damage. PATIENTS AND METHODS In this observational, single-center study, all patients intended for TKI treatment were analyzed for coronary artery disease (CAD) risk factors, history or evidence of CAD, hypertension, rhythm disturbances, and heart failure. Monitoring included assessment of symptoms, ECGs, and biochemical markers (ie, creatine kinase-MB, troponin T). Echocardiography was performed at baseline in selected patients and in all patients who experienced a cardiac event. A cardiac event was defined as the occurrence of increased enzymes if normal at baseline, symptomatic arrhythmia that required treatment, new left ventricular dysfunction, or acute coronary syndrome. RESULTS A total of 86 patients were treated with either sunitinib or sorafenib. Among 74 eligible patients, 33.8% experienced a cardiac event, 40.5% had ECG changes, and 18% were symptomatic. Seven patients (9.4%) were seriously compromised and required intermediate care and/or intensive care admission. All patients recovered after cardiovascular management (ie, medication, coronary angiography, pacemaker implantation, heart surgery) and were considered eligible for TKI continuation. Statistically, there was no significant survival difference between patients who experienced a cardiac event and those who did not experience a cardiac event. CONCLUSION Our observations indicate that cardiac damage from TKI treatment is a largely underestimated phenomenon but is manageable if patients have careful cardiovascular monitoring and cardiac treatment at the first signs of myocardial damage.

Hypothyroidism in patients with renal cell carcinoma: blessing or curse?

Sunitinib and sorafenib are tyrosine kinase inhibitors that have important antitumor activity in metastatic renal cell carcinoma (mRCC). Hypothyroidism constitutes a commonly reported side effect of both drugs, and particularly of sunitinib. The objective of this analysis was to investigate whether the occurrence of hypothyroidism during treatment with sunitinib and sorafenib affects the outcome of patients with mRCC.

Lung Transplantation for Bronchiolitis Obliterans After Allogeneic Hematopoietic Stem Cell Transplantation: A Single-center Experience

Background Bronchiolitis obliterans (BO) is a detrimental late pulmonary complication after allogeneic hematopoietic stem cell transplantation (HCT) associated with chronic graft-versus-host disease (cGvHD). When systemic immunosuppressive treatment fails to improve, severe BO patients should be considered for lung transplantation (LuTX). We present seven patients undergoing LuTX for severe refractory BO after HCT. Methods Seven patients with hematologic malignancies developed severe cGvHD with lung involvement presenting as BO after allogeneic HCT. Evaluation for LuTX was initiated after failure of a median of 4 immunosuppressive regimens. Results Between 1996 and 2012, seven patients with severe refractory BO were evaluated for LuTX. The median time from HCT to diagnosis of chronic lung GvHD was 8.2 months (range, 3.7–16.6). At a median time of 18.1 months (range, 6–120) after diagnosis of BO, six patients received a bilateral sequential LuTX, and one patient received a single LuTX. Six postoperative courses were uneventful; the patient with single LuTX died from septic multiorgan failure. Three LuTX recipients had a mild acute rejection after one to three months after LuTX, and one patient experienced fatal chronic rejection and hemolytic uremic syndrome. At present, three (43%) LuTX recipients remain alive at a median observation time of 26 months (range, 1 month–16 years) after LuTX. The median overall survival from LuTX was 24 months (95% CI, 0.5–78); the median overall survival time after allogeneic HCT is 98 months (95% CI, 46–198). Conclusion This case series illustrates that LuTX is a possible therapeutic option for selected patients with severe treatment-refractory BO.

Extracerebral metastases determine the outcome of patients with brain metastases from renal cell carcinoma

BackgroundIn the era of cytokines, patients with brain metastases (BM) from renal cell carcinoma had a significantly shorter survival than patients without. Targeted agents (TA) have improved the outcome of patients with metastatic renal cell carcinoma (mRCC) however, their impact on patients with BM is less clear. The aim of this analysis was to compare the outcome of patients with and without BM in the era of targeted agents.MethodsData from 114 consecutive patients who had access to targeted agent were analyzed for response rates (ORR), progression free survival (PFS) and overall survival (OS). All patients diagnosed with BM underwent local, BM-specific treatment before initiation of medical treatment.ResultsData of 114 consecutive patients who had access to at least one type of targeted agents were analyzed. Twelve out of 114 renal cell carcinoma (RCC) patients (10.5%) were diagnosed with BM. Systemic treatment consisted of sunitinib, sorafenib, temsirolimus or bevacizumab. The median PFS was 8.7 months (95% CI 5.1 - 12.3) and 11.4 months (95% CI 8.7 - 14.1) for BM-patients and non-BM-patients, respectively (p = 0.232). The median overall survival for patients with and without BM was 13.4 (95% CI 1- 43.9) and 33.3 months (95% CI 18.6 - 47.0) (p = 0.358), respectively. No patient died from cerebral disease progression. ECOG Performance status and the time from primary tumor to metastases (TDM) were independent risk factors for short survival (HR 2.74, p = 0.001; HR: 0.552, p = 0.034).ConclusionsAlthough extracerebral metastases determine the outcome of patients with BM, the benefit from targeted agents still appears to be limited when compared to patients without BM.

Safety and efficacy of temsirolimus in heavily pretreated patients with metastatic renal cell carcinoma

Background. First line treatment with temsirolimus is considered standard of care in poor risk patients with metastatic renal cell carcinoma. The role of temsirolimus in pretreated patients with any risk profile is unclear. The aim of this retrospective analysis was to investigate the impact of temsirolimus in patients who had progressed on various treatment lines. Material and methods. From April 2007 to July 2009, all patients who had progressed on receptor-tyrosine kinase-inhibitors, VEGF-antibodies and other agents were treated with temsirolimus (25 mg weekly). Physical examination, white blood cell count and chemistry were obtained weekly and tumor response was assessed every 12 weeks. Results. Thirty patients with a median age of 68 years range (44–81) received treatment with temsirolimus. Most patients were categorized intermediate risk (60%) and the majority had three or more metastatic sites (56.7%). Temsirolimus was median the fourth (range 2–5) systemic treatment line. Grade 3 and 4 toxicities were rare and consisted of anemia, thrombocytopenia and hyperglycemia. Objective remission and stable disease were achieved in 13.3% and 60% of the patients, respectively. The median progression free survival was 4.9 months (2.93–6.81 95% CI). Conclusion. Temsirolimus appears feasible, safe and active in heavily pretreated patients.

Fatal skin and pulmonary infection caused by Hormographiella aspergillata in a leukaemic patient: case report and literature overview

Invasive systemic fungal infections are a major cause of morbidity and mortality in patients after hematopoietic stem cell transplantation. We report the case of a fatal infection with Hormographiella aspergillata in a patient undergoing allogenic peripheral blood stem cell transplantation for acute myeloid leukaemia.

Cortical porosity not superior to conventional densitometry in identifying hemodialysis patients with fragility fracture

Hemodialysis (HD) patients face increased fracture risk, which is further associated with elevated risk of hospitalization and mortality. High-resolution peripheral computed tomography (HR-pQCT) has advanced our understanding of bone disease in chronic kidney disease by characterizing distinct changes in both the cortical and trabecular compartments. Increased cortical porosity (Ct.Po) has been shown to be associated with fracture in patients with osteopenia or in postmenopausal diabetic women. We tested whether the degree of Ct.Po identifies hemodialysis patients with prevalent fragility fractures in comparison to bone mineral density (BMD) assessed by dual X-ray absorptiometry (DXA). We performed a post-hoc analysis of a cross-sectional study in 76 prevalent hemodialysis patients. Markers of mineral metabolism, coronary calcification score, DXA-, and HR-pQCT-data were analyzed, and Ct.Po determined at radius and tibia. Ct.Po was significantly higher in patients with fracture but association was lost after adjusting for age and gender (tibia p = 0.228, radius p = 0.5). Instead, femoral (F) BMD neck area (p = 0.03), F T-score neck area (p = 0.03), radius (R) BMD (p = 0.03), R T-score (p = 0.03), and cortical HR-pQCT indices such as cortical area (Ct.Ar) (tibia: p = 0.01; radius: p = 0.02) and cortical thickness (Ct.Th) (tibia: p = 0.03; radius: p = 0.02) correctly classified patients with fragility fractures. Area under receiver operating characteristic curves (AUC) for Ct.Po (tibia AUC: 0.711; p = 0.01; radius AUC: 0.666; p = 0.04), Ct.Ar (tibia AUC: 0.832; p<0.001; radius AUC: 0.796; p<0.001), and F neck BMD (AUC: 0.758; p = 0.002) did not differ significantly among each other. In conclusion, measuring Ct.Po is not superior to BMD determined by DXA for identification of HD patients with fragility fracture.

Umbilical Cord Blood Transplantation Is a Feasible Rescue Therapeutic Option for Patients Suffering from Graft Failure after Previous Hematopoietic Stem Cell Transplantation

Objective: Umbilical cord blood (UCB) is an important graft source for hematopoietic stem cell transplantation (SCT). Due to less stringent human leukocyte antigen (HLA) matching criteria compared to bone marrow or peripheral blood stem cells, UCB enables patients lacking an HLA-matched donor to receive potentially curative SCT. Methods: We retrospectively analyzed the efficacy and safety of UCB transplantation (UCBT) at our center. Results: Between June 2009 and June 2015, 27 UCBT were performed in 25 patients. Reasons for the use of UCB were lack of adequate related or unrelated stem cell donor (n = 20) and graft failure after previous SCT (n = 7). Median time to neutrophil engraftment was 22 days. Four patients experienced primary graft failure. Thirteen patients developed acute graft-versus-host disease (GVHD), whereupon 6 subsequently also developed chronic GVHD. After a median follow-up time of 19 months, 9 patients relapsed and 12 patients died. Cause of death was relapse in 8 and transplant-related events in 4 patients. Median overall survival and progression-free survival have not been reached yet. Conclusion: In our experience, UCBT is an alternative graft source for patients lacking a suitable related or unrelated donor and a feasible treatment option for patients experiencing graft failure after previous SCT.

Haematopoietic stem cell transplantation for treatment of primary CNS lymphoma: single‐centre experience and literature review

Primary central nervous system lymphoma (PCNSL) is a rare and malignant tumour type. Established treatment approaches include high‐dose methotrexate (HD‐MTX)‐based chemotherapy and whole‐brain radiotherapy (WBRT). WBRT is associated with significant neurotoxicity and autologous haematopoietic stem cell transplantation (ASCT) has been proposed as an alternative treatment – either in the 1st line setting after HD‐MTX‐based chemotherapy or as salvage treatment for relapsed/refractory PCNSL. We here report our single‐centre experience with five PCNSL patients, who had achieved an objective response after a high‐dose methotrexate‐based induction therapy and consecutively received a high‐dose chemotherapy, consisting of carmustine and thiotepa, followed by ASCT. We also provide a literature review on ASCL for PCNSL. Our data, with three of five patients in continuous complete remission and four of five patients alive after a median follow‐up time of 8 months, as well as previously published results, show that ASCT is a safe treatment option that is able to induce tumour remissions in patients with PCNSL. However, controlled trials are needed to compare the long‐term efficacy and tolerability of ASCT with other treatment approaches and also to establish the optimal sequence of treatment regimens in PCNSL patients.

Clofarabine/cyclophosphamide for debulking before stem cell transplantation.

Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative rescue therapy for patients (pts) with chemotherapy‐refractory acute leukaemia. Disease control prior to HSCT is essential for long‐term disease‐free survival after HSCT.